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Saturday, April 23, 2016

A Lyme disease study published a few weeks ago in the New England Journal of Medicine has received a lot of coverage in the press. According to the abstract of the study, Berende and colleagues conducted a randomized placebo-controlled clinical trial to test the effectiveness of long-term "longer-term" antibiotics in treating "longer-term" chronic symptoms "attributed" to Lyme disease.

As many readers of this blog know, treatment of Lyme disease is a controversial topic. Antibiotics are effective in treating Lyme disease, but
10-20% experience symptoms such as fatigue, muscular aches,
and joint pain for at least 6 months following conventional treatment. The cause of the persisting symptoms is not known. They could be
due to tissue damage caused by the infection, ongoing inflammation, or bacteria that survived antibiotic treatment. Mainstream medical societies such as the IDSA do not believe that lingering infection is responsible for the persisting symptoms, and they do not recommend retreatment with antibiotics. Four randomized controlled studies conducted in the U.S. showed little benefit of
retreating these patients with antibiotics for up to 3
months. On the other hand, not-so-mainstream groups such as ILADS
dispute the interpretation of the data. They insist that the treatment
groups did show some improvement and that longer
treatment regimens lasting longer than 3 months are needed for complete recovery of these patients.

There is another group of patients that also suffer from enduring fatigue, muscle aches, and joint pain. They may or may not have had Lyme disease in the past, but their ongoing symptoms stem from some other condition. Unfortunately, they may be misdiagnosed with "chronic Lyme disease" and end up being treated for a long time with antibiotics in an attempt to eradicate an infection that they don't have.

The new NEJM paper describes a randomized placebo-controlled trial that
was conducted in the Netherlands. 281 subjects who had been experiencing chronic symptoms blamed on Lyme disease (fatigue, muscle aches, joint pain) were randomized into three groups. All three
groups were treated with ceftriaxone intravenously for two weeks. The subjects were next given oral antibiotics or placebo for 12 weeks.
One group was treated with doxycycline, another group with both
clarithromycin and hydroxychloroquine, and the third group was given
placebo pills.

The graph below shows that the physical quality of life, the primary outcome measure, improved a little for all groups. Because there was no difference in outcome among the three groups, the authors concluded that longer-term antibiotics were no better than short-term antibiotics in alleviating symptoms. We don't know whether the initial two-week treatment with ceftriaxone had anything to do with the slight
improvement since there was no true placebo (antibiotic-free) group.

Why wasn't a true placebo group? The authors worried about withholding antibiotics from subjects who might have an infection that should be treated. 11% of the subjects hadn't been treated with antibiotics for their symptoms prior to their acceptance into the study. This wasn't an issue with the earlier U.S. trials since previous treatment of Lyme disease with antibiotics was a requirement for acceptance into those studies, which included true placebo groups.

One baffling aspect of the study was the inclusion of subjects who might not have had Lyme disease prior to the appearance of their chronic symptoms. Only a third of the subjects had objective clinical features of Lyme disease (erythema migrans, meningoradiculitis, or acrodermatitis chronica atrophicans) immediately preceding their chronic symptoms, and a little more than a half recalled a tick bite. Contrast this with the earlier U.S. studies, which only accepted patients with chronic symptoms
that followed antibiotic treatment of a well-documented case of Lyme disease.

The remaining subjects did not have any objective features of Lyme disease before their chronic symptoms appeared. The only evidence of a previous episode of Lyme disease was positive antibody testing by Western blot. However, the antibodies may have been elicited by a Borrelia infection in the distant past. Their past episode of Lyme disease may not be related to their chronic symptoms, which aren't specific for Lyme disease. Another problem with relying solely on Western blots to diagnose Lyme disease is that false positives occur. Without additional evidence, it is hard to be sure that their chronic symptoms were related to Lyme disease.

Nevertheless, the editorial accompanying the paper expressed support for the relaxed inclusion criteria used to select the subjects for the study:

Critics may rightly say that this trial does not
truly capture with certainty the consequences of
bona fide Lyme disease. However, studies with
more stringent inclusion criteria have already been
conducted, and the approach used by Berende
and colleagues probably reflects the common
practice in ambulatory care settings, in which
patient presentations of fatigue or nonspecific
pain prompt serologic checks for Lyme disease,
despite evidence suggesting that these tests will
not identify a probable cause or result in a treatment
benefit.

The study population may reflect what's encountered by clinicians in the real world, but for a clinical trial it doesn't seem right to lump those whose chronic problems followed a real episode of Lyme disease with those whose issues had nothing to do with Lyme. Any benefit of the antibiotics experienced by those who had genuine Lyme disease (assuming that there was any benefit) may have been obscured by the lack of benefit in those whose chronic symptoms aren't related to Lyme disease.

Berende and colleagues also defended the length of treatment, which is considered to be on the short end by those who support lengthy courses of antibiotic therapy:

...it may be argued that 14 weeks of
treatment is insufficient to show a beneficial
treatment effect. However, whereas prolonged
antimicrobial treatment is not uncommon for
various infectious diseases, the purpose of
prolonged therapy for such diseases is for the
prevention of microbiologic relapse rather than
for a delayed onset of clinical alleviation of signs
or symptoms. We are not aware of any infectious
disease in which the initial effect on signs,
symptoms, and laboratory findings is delayed
beyond the first 3 months of effective therapy.

But the graph above clearly shows that the subjects felt better following the treatment period. Unfortunately, as I mentioned earlier, the improvement in the quality of life can't be attributed to the antibiotics because there was no true placebo group.

With these issues, I'm not sure how this study got published in NEJM. Regardless of my opinion, it will undoubtedly be cited as further proof that long-term antibiotics don't alleviate long-term symptoms that stem from Lyme disease.

Feeding Ixodes ticks harboring Borrelia burgdorferi deposit the Lyme disease spirochete in the skin of the victim. The spirochetes remain...

Common Spirochete Diseases

Lyme disease is a tick-borne disease caused by several members of the Borrelia burgdorferi complex. B. burgdorferi, B. garinii, and B. afzelii account for most cases worldwide. A rash may appear at the site of the tick bite, and the patient may experience flu-like symptoms. Left untreated, the patient may suffer from neurologic, arthritic, and cardiac complications.

The syphilis agent Treponema pallidum is most commonly acquired by sexual contact. A skin lesion called a chancre appears at the site of initial contact with the spirochete. T. pallidum later spreads to other sites in the body to cause the flu-like symptoms and rash of secondary syphilis. Once secondary syphilis resolves, the spirochete may persist for years without causing problems. Later, tertiary syphilis can result in damage to vital tissues. Neurosyphilis and cardiovascular syphilis are two common forms of tertiary syphilis.

Leptospira lives in the kidneys of rodents and other reservoir hosts and is shed via urine into the environment. Humans acquire the spirochete by contact of abraded skin or mucous membranes with infectious urine or contaminated water or soil. Leptospirosis patients may initially experience flu-like symptoms. Jaundice and impaired kidney function occur in the potentially deadly form of leptospirosis called Weil's disease.